Franklin Institute

/"he JO URNAL

OF THE FRANKLIN INSTITUTE

OF THE STATE OF PENNSYLVANIA

DEI"OTED 7"0 SCIENCE AND THE MECHANIC ART8

VOL. CLXXII AUGUST, I9II No. 2

THE CHEMISTRY O.F ANZESTHETICS.*

BY CHAS. BASKERVILLE, Ph.D., F.C.S., Professor of Chemistry, College of the City of New York.

SACRED, profane and mythological literature abound in inci- dent, fact and fancy, showing that from earliest times man has sought to assuage grief and pain by some means of dulling con- sciousness. Recourse was had to the inhalation of fumes from various substances, weird incantations, applications of drugs, both external and internal, pressure upon important nerves and blood- vessels, and the laying on of hands, or animal magnetism. Each has played its part in the mitigation of human ills. It was not until the close of the eighteenth century~ however, that modern surgical anaesthesia was foreshadowed. Then it was that the discovery of hydrogen, nitrogen, oxygen, and nitrous oxide pneumatic chemistry, as it were--created a field of pneumatic medicine. In I798, the Pneumatic Institute was founded for the purpose of investigating the "medical powers of factitious airs or gases " and was set up at Clifton by Dr. Thomas Beddoes. The immediate idea to be followed out was the treatment of phthisis and other lung troubles by inhalation of various gases. Hum- phrey Davy was assigned the omce of superintending the experi-

* Presented Wednesday evening, June 14, 1911. [NoTE.--The Franklin Institute is not responsible for the statements and opinions advanced by contributors to the JOURNAL.] Copyright, x9l t, by THE PRANKLIN INSTITUTR. VOL. CLXXII, No. 1028-"--9 113 I 14 CHAS. BASKERVILLE. ments. One of the first outcomes of his researches, the result of his experimentation with nitrous oxide upon animals, is given in the following historical and often quoted sentence1 : " As nitrous oxide in its extensive operation appears capable of destroying physical pain, it may probably be used to advantage during surgical operations in which no great effusion of blood takes place." Davy actually inhaled the gas, and recorded his own sensations and the behavior of others after they had inhaled it. In ~8o 5 Dr. Warren, of Boston, used " sulphuric ether " on a patient suffering with phthisis, and the year following it was used in attacks of asthma; but Faraday in I818 was the first to recognize its value as an anaesthetic. Chloroform was discovered in I83I independently by Liemg, Soubeiran and Guthrie. It is reported in the American Journal of £cience for January, I832, that Dr. Ires, of New Haven, used chloroform in surgery. In I828, Girardin read a paper describing surgical anmsthesia by means of inhaled gases ; but the honor of the discovery, of surgical anaesthesia has been claimed, with more or less acrimonious partizanship, for four others, namely, Long, of Jefferson, Ga., who anaesthetized a patient with ether in I84I ; Wells, of Hart- ford, Conn., who used nitrous oxide in dentistry in ~844; and Morton, a pupil of Wells, used ether instead, at the suggestion of Jackson, a chemist, who later claimed to be the real dis- coverer. Simpson, in I847, first used ether in midwifery and later he employed chloroform, whose an,esthetic properties had been previously descrit)ed by Flourens. In I868 Andrews, of Chicago, called attention to the use of oxygen with nitrous oxide to produce a non-asphyxial form of anaesthesia. In I9o6, Brown, of Cleveland, used a warmed mixture of nitrous oxide and oxygen, followed by ether and chloroform, with great success. In i9o 9, Gwathmey, of New York, moistened the gases. I need not recount the historical data which have to do with other anaesthetics, a list of which I have published in the American Druggist, and my remarks this evening will therefore be limited to nitrous oxide, ether and chloroform: and these

~Davy "Researches, Chemical and Philosophical, chiefly concerning Nitrous Oxide," London, i8oo. THE CHEMISTRY OF AN.ESTHETICS. II 5 few facts--the results obtained from careful unbiased investigation of the literature and other forms of evidence--are given without elaboration or argument. The writer knows of rio satisfactory basis of classification of anaesthetics. Some are general, others local, but the latter may become general in their effects, depending upon conditions. Hence, they will be considered in chronological order.

NITROUS OXIDE.

In 1772, Priestley first prepared nitrous oxide by reducing NO with moist iron filings. In 1793, Deiman and others prepared the gas by heating NH4NO~, essentially the commercial process for its manufacture to-day. It is usually carried out by heating mixed salts, as NaNO~ and (NH4)2SO4, NaNO3 and NH4C1, etc. 2 Commercial nitrous oxide is apt to contain these impurities: C12, NO, NO2, HNO3, NH~, HC1, CO., O2, N2, and the rare gases of the air. It is usually purified by passage through solutions of sodium hydroxide, ferrous sulphate, and sulphuric acid. Further purification may be accomplished by the formation of a hydrate 3 below 0 ° C. and heating this hydrate (N20,6H2'O)-- that is, by fractional condensation 4 and by fractional distillation. The following impurities may be suspected in a cylinder of compressed nitrous oxide: i. Solids. 2. Liquids. 3. Gases and vapors: H._,O, halogen acids, HNO3, organic acids, 0~, NO2, N~03, SO~, •NH3, organic bases, CO~., halogens, oxides of chlorine, HCN, (CN):, PH3, SbH,, ASH3, H~S, 02, H2, CO, CH4, organic matter (from valve lubricants), N2, rare gases of the air.

Baskerville and Stevenson, I. Ind. and Eng. Chem., iii, No. 8. s Villard, Compt. rend. (I894), cxviii, lO96. Stolzenberg, Ber., xliii, 17o8. I I6 CtlAS. BASKERVILLE.

For these impurities, a qualitative search should first be made and ~then, whenever necessary, a quantitative determination. A systematic procedure has been devised, a detailed account of which on this occasion would be unwelcome. Those substances known to be irritant to the respiratory organs should be tested for to make sure of their absence before the gas is used in surgical cases. It may be said that established manufacturers appre- ciate this and govern themselves accordingly, consequently it is not necessary to test every cylinder supplied by them. Their integrity constitutes an asset--a fact which, unfortunately, is not the case with all manufacturers of all drugs. Beyond the absence of disturbing impurities, the improved methods of the use of nitrous oxide for anaesthetic purposes de-

TABLE I. ANALYSIS.

i N~,ete N~Obyl N~Oby [N2Oby No.] N,O H~O CO2 NHs 02 by explo- Cu + CO~ [ Cu -- ai~. S!O~_ +~;__] m ! x / 99.7 I °'I3 I o o.oo6 present / o.16 97.5 ! 99.4 / 99-7 I 96"6 I °'15 I o o.oo i present / 3"25 / 95 .0 ! 96.2 ~ 9''0 3 | 99.5 h °'I5 / o o present / o.35 I97.3 I 99.5 ~ 9~.5 4195"9 /°'I6/ present o present /394194II 95.6 19.~0

mand a knowledge of the approximate content of nitrous oxide in the commercial product, as will become apparent later; hence a method for its determination is desirable. Various methods have been proposed--for instance, decomposition into N2 and 02, burning with hydrogen, explosion with hydrogen, combustion of charcoal with absorption of CO2 produced, explosion with CO, oxidation of a fused mixture of sodiuln carbonate and Cr~O3 and determining the amount Of Na2CrO4 produced, and absorption in alcohol; and none is satisfactory. Dr. Stevenson and the writer have devised a new method, which gives accurate results in hands skilled in the manipulation of gases. It depends upon passing a definite quantity of the gas over heated copper gauze, after a preliminary treatment to remove oxygen or compounds which produce copper oxide from the sample, and then passing hydrogen through the apparatus, and absorbing the water formed. THE CHEMISTRY OF ANAESTHETICS. 11 7

Table I, which is self-explanatory, exhibits the results of our analyses of compressed nitrous oxide as supplied by American manufacturers. Nitrous oxide which is-: to be used for anaesthesia, should contain at least 95 per cent. of N20 and no solids, liquids, combustible organic matter, chlorine, or other oxides of nitrogen. A small amount of carbon dioxide, according to the investigations of Gatch, can have no evil effects. If present, however, the percentage should be known.

ETHYL ETHER. Experiences of expert anaesthetizers, often not accounted for by idiosyncrasy, obtained in the use of ethyl ethers supplied by various manufacturers in numerous surgical cases, furnished the motive for this phase of the investigation of the chemistry of anaesthetics. The standards laid down by the various pharmacopoeias of the world are not uniform. In view of that fact alone, a thorough investigation seemed called for. Enquiries addressed • to large consumers of the solvent in manufacturing processes adduced further need for satisfactory methods of determining the purity of ethyl ether and of detecting impurities introduced, or proving their absence if eliminated, in the modification of raw products used in its manufacture. The presence of small amounts of substances has oftentimes been the cause of a chemical reaction proceeding in a particular direction by virtue of a " catalytic action." So the presence of even traces of certain substances, as peroxidized compounds, aldehyde, etc., may have caused some reactions to be incorrectly explained, or to follow an unusual, or unaccounted for, route. Ethyl ether is still made commercially by the historical process of treating alcohol with sulphuric acid--hence the misnomer of " sulphuric ether," or " vitriolic ether "--although other synthetic processes have been proposed, some of which have been tried out. but always without commercial success. In this connection reference may be made to the method devised by Fritsche for the preparation of ether free from alcohol. In this method gas containing ethylene is treated with sulphuric acid, 5 and the ethyl-sulphuric acid so obtained is con-

s Z. anal. Chem., xxxvi, 298; U. S. Patent No. 475,640, Jan. 19, 1897. II8 CHAS. BASKERVILLE. verted into ether and sulphuric acid by means of water. It was reported that this process was operated on a commercial scale in this country for some time, but that the industry was destroyed by the Denatured Alcohol ActY It is likely, however, that a similar industry may be revived, as natural gas might serve as a suitable material from which to prepare ether. 7 The quality of ethers on the market depend upon, first, the purity or grade of the alcohol used; and, second, secondary reactions which take place, not only with impurities in the alcohol, but with ethyl hydroxide itself. For example, ethyl ether made from ethyl alcohol denaturized by methyl alcohol contained other ethers, as dimethyl oxide or methyl-ethyl ether, not found in the ether made from the old rectified spirit. The generous interpretation of the denatured alcohol act by our Government officials, whereby alcohol denaturized by ether itself may now be used, eliminated these substances. Many of the impurities traceable not only to the quality of the raw products used, but the secondary reactions of their virgin impurities, due to variations, as in temperature, pressure, and other conditions, were removable and have in a large measure been removed, or much reduced, by subsequent purification. It was found necessary in our work to make discriminations in the various grades of ether, s so the following classification was settled upon and its adoption by others is suggested: I. Pure Ether.--Absolute ether---ether free from all impurities. 2. Anhydrous Ether.--Ether free from water, but which may contain traces of ethyl alcohol and acetaldehyde. 3. Ancesthetic Ether.--Ether complying with the pharmaco- pceial requirements. Such ether may contain ethyl alcohol (up to 4 per cent.), and traces of acetaldehyde, acids, and water, although in the opinion of the author, it is highly desirable that the three last mentioned,--i.e., the impurities,--be totally eliminated.

OBull. 9e, U. S. Dept. of Commerce and Labor, Bureau of the Census, I9o9, p. 95. • 7 Cf. French Patent 352,687, of I9O5, of Lance and Elworthy. 8 Chas. Baskerville and W. A. Hamor, ]. Ind. and Eng. Chem., iii, 3ox, 378. THE CHEMISTRY OF AN3ESTHETICS. I I 9

4. Commercial Ether.--Ether which contains at least 95 per cent. by weight of ethyl oxide. All other grades of ethyl_, ether should be classed as Impure Commercial Ether. The standard of purity for laboratory ether, or ether for analytical purposes, is entirely dependent upon the purpose for which it is intended. For ordinary reagent purposes, the grade specified under Ancesthetic Ether is suitable, and in general may be said to answer all such purposes; but in special cases the other ethers may be employed. Our attention will be confined to anaesthetic ether. The specific gravity of ether intended for anaesthesia should not exceed 0.720 at 15 ° C., providing an ether containing minimum quantities of alcohol and moisture is required; however, an ether which shows a specific gravity of o.7215 (2 per cent. absolute alcohol), 0.7228 (3 per cent. absolute alcohol) or even 0.724 (4 per cent. absolute alcohol), providing the sole "impurity " is ethyl alcohol, is acceptable for anaesthetic purposes according to various pharmacopoeias. In this connection it may be stated that for various reasons a pure ether may be diluted with ethyl alcohol when it is to be used for anaesthesia. Impurities then observed may be due in part to the alcohol used in dilution. Practically all ethyl alcohol contains some acetaldehyde. Ethyl alcohol serves, it is asserted, as a preservative for ether when the latter is properly stored; and small amounts interfere in no way with the application of ether in anaesthesia. However, the presence of alcohol is unnecessary except when ether is administered by the " drop method." In this case, the presence of alcohol prevents too rapid volatilization and conse- quent chilling of the apparatus with which the ether is administered. Some have maintained that pure ethyl ether is unsuitable for anaesthesia, but it is a fact that the vapor from ether containing alcohol, when passed through water at 4 °0 C., whereby the alcohol is removed, may be and is being used now with great success for anaesthesia. The presence of excess moisture in liquid ether should 'be guarded against, since ether in contact with water, or moist air, in time gives rise to various impurities of an objectionable nature. Thus anaesthetic ether even of proper grade may develop impurities to be avoided quite as VOL. CLXXII, No. lO28--1o 120 CHAS. BASKERVILLE. much as if they had been introduced in the original materials or later produced in the manufacture or added in the preparation for distribution in commerce. Instances of sophistication have been known, but now they are comparatively rare. There are more frequent instances of contamination resulting either from the lack of control in the manufacture or from careless storage. It is almost needless to call attention to the necessity for having a substance such as anaesthetic ether, which is used so extensively in the most critical cases, as pure as human ingenuity can provide it. Traub pointed out that a sample of "impure " ether usually leaves a fruity odor when allowed to evaporate on filter paper, and it is generally recognized that filter paper which has been moistened with ether must possess no odor after the evaporation of the ether. This test is given in the pharmacopceias of Austria, Belgium, Japan, Switzerland, Spain, Great Britain, Germany, and the United States. Generally a positive result may be said to be indicative of the presence of " heavy oil of wine," amyl, propyl, or butyl compounds, or fusel oil. These materials, if present, may excite coughing during inhalation. The occurrence of fusel oil and of " heavy oil of wine " is rare in the case of anaesthetic ethers and they are really only likely to occur in commercial and impure commercial ethers. Ether, when freshly distilled over sodium, possesses a specific gravity of o.7178 to o.7I 9 at I5/4 ° C. ; but if it is not, immediately after its rectification, drawn off into vessels, which are sealed at once and carefuly stored, the specific gravity increases in a short time. The purest ether procurable on the market is of o.718-o.7I 9 specific gravity at I5% but this absorbs water on exposure to the atmosphere, and rises to o.72o-o.72I specific gravity, when it becomes fairly constant. Since the specific gravity of ether is o.7178 to o.719 at I5 ° C., those requiring ether of 0.720 specific gravity thus allow minimum amounts of water and alcohol. Unless the ether is dried carefully by means of sodium, for example, and is kept constantly dehydrated by storing over such an agent, or great care is taken in storing 'it after final rectification, it is practically impossible to maintain the specific gravity originally possessed by the ether. The ethers recognized as official by the pharmacopoeias of various countries possess the specific gravities shown in Table II. THE CHEMISTRY OF ANJESTHETICS. 12I

Although the boiling point of pure ether is + 34.6 ° at 760 mm., there are no ethers of anaesthetic grade on the market which comply fully with this requirement, owing to the mutually oppos- ing influences of water and alcohol on the boiling point, and only ether distilled over sodium closely approximates it. Since, therefore, these influences render the constancy of the boiling point as ordinarily determined of little or no use as a criterion

TABLE II. Specific gravity. Countries where recognized. o.716-o.717 ...... United States. 0.72o ...... Russia; Great Britain; Mexico; Spain; Japan; Ger- many; France; Belgium; Sweden; Holland; Hun- gary. 0.720-0.722 ...... Switzerland ; Italy ; Norway ; Denmark. o.725 ...... Austria. 0.724-o.728 ...... Finland. 0.728 ...... Portugal. of purity, it is sufficient to require that ether shall commence to distil at a temperature not under -}-34 ° C., and that it shall possess a boiling point of -F- 34 ° to 36° C. We have found that ether purified by distillation over sodium yields a distillate amounting on the average to 99.5 ° per cent. of the total amount taken when fractioned, this percentage distilling off between + 34 ° to 35 ° C. ; whereas three ethers used for anaesthesia gave the results shown in Table nI.

TABLE III." Temperature. Percentage by volume. I. II. III. 25o-34 ° ...... I.OO I .OO I.OO 340-360 • ...... "...... 98.50 97 .00 97.50 360-37 ° • ...... 0.50 2.00 1.5o 370-42 ° ......

In view of these facts, augmented by other experiments, the writer is of the opinion that ether intended for anaesthetic purposes should, when carefully fractionated, yield a distillate amounting to at least 97 per cent. by volume between + 34 ° and + 360 C., and that not more than I per cent. should distil off: below -+ 34 ° C., if it is to comply with present pharmacopoeial requirements. 122 CHAS. BASKERVILLE.

Ethers recognized as official by various countries possess the boiling points shown in Table IV. The writer, assisted by Mr. W. A. Hamor, has conducted an extensive investigation of the changes which occur in ethyl ether during storage, and the experimental data obtained lead to the conclusion that the oxidation of ether in the presence of moisture is productive of a series of complex conversions, initi- ated, however, by the formation of hydrogen dioxide. The slow combustion of pure ether in the presence of water, and under such conditions as exist when it is improperly stored, would appear to occur in the following stages: I. The formation of hydrogen dioxide from water and oxygen of the air. This is particularly likely in cases where there TABLE IV. Boiling po~.nt. Where recognized: 34.5 ° ...... Great Britain. 34o-36 °...... Finland ; Austria. 35 °...... Hungary ; Japan ; Germany ; Belgium ; Russia. 35.5 ° ...... United States. 350-36 ° ...... Switzerland. 36* ...... Italy ; Norway ; Denmark ; Portugal ; Holland. 36.5 ° ...... France. is direct exposure to light, and it is more or less activated by contact action. 2. Dissociation of hydrogen dioxide into water and oxygen, which latter then exerts a direct oxidizing action, resulting in the formation of the following: acetic peroxide;acetaldehyde and acetaldehyde peroxide; and eventually acetic acid. The formation of acetic peroxide would facilitate a series of oxidations, and by its hydrolysis alone, acetic and.peracetic acids would be formed. The peracetic acid would then become converted into acetic acid and hydrogen dioxide; therefore, it is reasonable to conclude that a continuous cycle of changes occurs in the ether during its oxidation and that such changes result in the simul- taneous formation and occurrence of peroxidized compounds, intermediate (aldehyde) and ultimate (acetic acid) resultants. When anhydrous ether is exposed to the action of atmospheric oxygen during improper storage, there is every reason for the conclusion that peroxidation occurs ; such action is similar to that which takes place when anhydrous ether is ozonized, but THE CHEMISTRY OF ANESTHETICS. i2 3 the process is much less active, being indirect. During storage under conditions which would be conducive to oxidation, the absolute exclusion of moisture is not attained. Changes occur similar to those which ensue in the presence of water, but of a much slower and much less intense nature. Our experimental work seems to establish beyond any doubt the fact that ether of anesthetic grade contains peroxidized compounds after exposure to varying temperature conditions and sunlight, in the presence of atmospheric oxygen, for considerable periods of time, especially when it is stored in colorless glass vessels, or in badly stoppered tin containers. Acetaldehyde, the presence of which may account for some of the observations made in practice, is one of the impurities most likely to be generated by exposing partially filled containers to varying atmospheric conditions for continued periods of time. Ether should not be stored in glass vessels for any length of time without being tested for oxidation products before use; and the tin containers should be of such capacity that they need not be opened without being emptied when the ether is employed for anaesthetic purposes. The sealing of tin containers will be referred to later. With regard to the acidity of the various anaesthetic ethers on the American market, it may be said that none that we have examined contained acids (sulphurous, sulphuric, acetic) in what may be termed injurious amounts, since the amount present never exceeded 0.002 Gm. of acetic acid per Ioo c.c. of the sample in any case. The degree of acidity is liable to vary more or less in both directions in short intervals during storage in glass vessels, just as in the case of the oxidation of ether itself. The variations in acidity--theoretical, but not sensible in general-- may be due to differences between the rapidity of the oxidation and the saturation of the acids by the bases of the glass. In fact, it should be mentioned here that the nature of the ether container is of vast importance in the light of the oxidation changes which are possible. The extent of the oxidation--or, for that matter, any oxidation at all--is dependent upon the quality of the glass used in bottles for storing ether; and in the case of metallic containers, in view of some recent researches, it is probable that all metals which show anomalous anodic conductivity are likely to develop free hydrogen dioxide in contact with water 12 4 CHAS. BASKERVILLE. and oxygen. ~ The presence of such metals should, therefore, b'e guarded against. Since it is highly important that ether intended for anesthetic purposes should be carefully manufactured and properly stored, as prolonged exposure to light and air greatly affect "the results of etherization, causing coughing, suffocation, and even dangerous after-effects, such ether should always be tested for peroxides and aldehyde, and the presence of the latter should be rigorouslyguarded against, or the ether, if so contaminated, should be administered by a method which eliminates these impurities before it is introduced into the animal system. We have made an examination as to the value of all proposed tests for the impurities in ethyl ether and devised several new and superior ones. A scheme for examination has been worked out and is now available in the literature. 9

CHLOROFORM. Liebig prepared chloroform from chloral. Soubeiran treated alcohol with "bleaching powder." Schering generated his "bleach" in the presence of alcohol by electrolysis. Then " methylated spirit " was used, whereby so-called " methylated chloroform" was obtained. Liebig also obtained chloroform by the action of " chloride of lime " upon acetone. B6ttger and others used acetates (I848), and then chlorine was liberated in acetone by electrolysis. This process is used extensively in this country now. Methane of natural gas has been burned in chlorine, but this process has not proved successful commercially so far, although " gas chloroform " is spoken of by some in a wise way. Carbon tetrachloride, made by chlorinating carbon disulphide, is being reduced by the process of Smith to produce much chloroform in this countl-y at present. " Chloral Chloroform " is imported in small quantities. From the variety of "ausgangs-material " and different methods used, it is quite evident that crude chloroform may contain a wide range of impurities, which may vary not only with the materials used, but the conditions of manufacture. Alcohol has been removed from chloroform by washing with water, the chloroform being subsequently dried over calcium

I. Ind. and Eng. Chem. iii, 395- THE CHEMISTRY OF AN2ESTHETICS. 12 5 chloride. Potassium hydroxide has been used to remove excess chlorine and acids. Manganese dioxide has been used to remove sulphur dioxide. Chloroform has been treated with concentrated sulphuric acid until the acid was no longer colored, and then the vapors of chloroform have been passed through towers of crystallized sodium carbonate; rectification has followed. To remove special impurities or decomposition products of the chloroform itself, chloroform has been treated with lead dioxide; with potassium p~rmanganate, or with dilute sodium thiosulph- ate; or it has been distilled over 2 per cent. paraffin or poppy oil. " Chloroform Anschfitz " is obtained by distilling from crystals of salicylid-chloroform (~2sH160s.2CHC13). "Chloro-

TABLE V. DETERMINATIONS OF THE SPECIFIC GRAVITY OF CHLOROFORM. o 0 ...... 1.52523, 1.52657 I~.8 °. ..1.5o39 12 °. .... x.496, 1.512 15 ° ..... 1.485, 1.4946, 1.49o5, 1.4976 , 1.5o66, 1.51o7, 1.4989, 1.498o, 1.5oo , 1.5oo27, 1.5oo85, 1.49887 (Baskerville and Harnor). 15.5 °.. .1-5oo 16.5°...1.472 17 ° ..... 1.491 , 1.5o7 18 ° ..... I. 48 18.58% . 1.48978 25 ° ..... 1.48432, 1.48492 29 ° ..... I. 49o89 35.86o.. 1.45695 60.8 ° ... I. 4o81 61.2°... 1.4o877 63 ° ..... 1.3954, 1.4o18, 1.4o8114 form Pictet " is made by chilling chloroform to --8o ° C., filter- ing off the solids produced, and then lowering the temperature to --82 ° C. and drawing off the liquid impurities. The frozen chloroform is then fractioned, the intermediate 80 per cent. of the distillate being taken. The specific gravity values of chloroform have been determined by different workers 10 as shown in Table V. In the course an investigation of the decomposition of chloroform, we prepared pure chloroform. This possessed a density of 1.49887 at 15/4 ° C. (average of six determinations), a result in close agreement with the values of Thorpe and

10 Chas. Baskerville and W. A. Hamor, 1. Ind. and Eng. Chem., iii. 126 CHAS. BASKERVILLE.

Timmermans. This value may be taken as the correct specific gravity at the temperature noted. The anaesthetic chloroform on the American market varies in specific gravity from 1.473 ° to 1.4827 at 25/25 ° , usually in close proximity to 1.476, the minimum density perm. itted by the Pharmacopwia. The samples of chloroform of German manufacture examined varied in specific gravity from 1.487to 1.492 at 15/15 °, although one sample possessed a density of 1.497 at this temperature. Since the correct specific gravity of chloroform is 1.49887 at 15/4 ° , those officials requiring chloroform of lower density--that is, anaesthetic chloroform--allow the addition of alcohol, and congequently the presence of small amounts of water; the permissible addition usually varies from o.25 to I per cent. Specific gravity determinations are not to be regarded as criteria of purity beyond indicating the amount of alcohol in chloroform. The chloroform constants according to various editions of the United States Pharmacopoeia are as follows:

Date. Density at x5° Boiling point. 1851 1.49 142o F. 1869 1.49o-1.494 14o° F. 1873 1.48o 142° F. I882 1.485-1.49o 6o-61 ° C. 1893 Not below 1.49o 6o-61 ° C.

The specific gravities of the chloroform recognized as official by the pharmacopoeias of various countries are given in Table VI. The boiling points of anaesthetic chloroform recognized as official by the various pharmacopoeias are shown in Table VIII. In general, it may be said that no specific directions are given in the pharmacopoeias for the determination of the boiling point and the influence of the variables (alcohol and water in particular) has not received enough attention. Opinions are divided as to the value of the determination as a criterion of the purity of anmsthetic chloroform. In the writer's opinion, it is of no value without a knowledge of the content of alcohol and water. In making a careful fractionation of 500 Gm. of anmsthetic chloroform made from acetone, containing 0. 5 per cent. alcohol and o.o26 per cent. water, but otherwise pure, the temperature THE ,CHEMISTRY OF AN.ESTHETICS. I2 7

TABLE VI.

DENSITIES ACCORDING TO VARIOUS PHARMACOP(EIAS.

1.48o ...... Spain ; Portugal ; Mexico. 1.489 ...... Switzerland. 1.49o ...... Greece. 1.497 ...... Chili. 1.498 ...... France. 1.5oo ...... Romania. 1.485-I.489 ...... Germany; Denmark, Hungary; Norway; Sweden; Finland. 1.485-I.49o ...... Belgium. 1.485-1.495 ...... Japan. 1.485"I .5oo ...... Austria. 1.49o-1.495 ...... Italy. 1.49o-I.495 ...... Great Britain. 1.498-I .5o0 ...... Holland. 1.49o-1.50o ...... Ru,ssia. Not below 1.476 at 25 ° ...... United States.

TABLE VII.

BOILING POINTS OF CHLOROFORM DETERMINED BY DIFFERENT SAVANTS.

Year, Observer. Temperature.

I883 Schiff 60.9 ° at 754.3 mm. I884 Perkin 62.0 ° at 760 ram. I885 Bauer 6z.o ° at 760 ram. 61.6 ° at 76omm. I899 Thayer I 61.64 ° at 76o ram. I899 Pettit 61.97°at 760 ram. I9O4 Wade and Finnemore . 6i.i 5 ° at 76o ram. i9II The Author 6*.2o°at 760 ram.

TABLE VIII.

CHLOROFORM BOILING POINTS ACCORDING TO VARIOUS PHARMACOP(EIAS.

59.5-61.5 ° ...... Sweden. 50°...... Italy. 5o.8 °...... Spain ; France; Chili; Romania. 61 °...... Mexico ; Greece. 5o°-61 °...... United States ; Russia. 50°-62 °...... Great Brltain; Germany; Austria; Switzerland; Bel- gium ; Denmark; Norway; Japan ; Finland. 51.3 ° ...... Holland. 61 °-62 ° ...... Hungary. I28 CHAS. BASKERVILLE. * rose at once to + 55.5 ° C.; at which point part of the alcohol and water with some chloroform passed over, the remainder going over between + 59.4 ° and + 61 °. The following fractions were obtained : Temperatures. Weight of fraction. 55.5-59.4 ° IO Gm. 59.4-61.o ° 177 Gm. 61.o"61.2 ° 300 Gm. Above 61.2 ° x3 Gm. The influence of alcohol and water, separately or together, on the boiling point of chloroform, may be seen from Table IX. There has been not a little diversity of opinion among chemists as to the nature and products of the decomposition of chloroform, especially the changes which chloroform undergoes upon exposure to air; in fact, this discordance dates from the introduction of chloroform as an anmsthetic and prevails to-day. This condition is ascribable to the many influencing factors occasioned by the degree of purity of the chloroform under examination, the

TABLE IX.

BOILING POINTS OF MIXTURES OF CHLOROFORM, ALCOHOL AND WATER. Per cent. Constituents. chloroform. Boiling point. I. Chloroform-alcohol-water ...... 92.5 55.5 ° 2. Chloroform-water ...... 97.5 56.1 ° 3. Chloroform-alcohol ...... 93.o 59.4 ° 4. Chloroform ...... ioo.o 61.2o ° 5. Alcohol-water (95-5 per cent. alcohol)... 78.15 ° 6. Alcohol ...... 78.3 ° 7. Water ...... IOO.OO°

extent and nature of the exposure; but is principally due to the failure to consider, and therefrom to correctly interpret, the r61e of the general variable, alcohol, and with it the accompanying moisture. The products of the decomposition of "pure " chloroform, according to various investigators, may be thus summarized:

Chlorine; hydrochloric acid: Morson; Maisch; and Hager. Carbonyl chloride : Rump ; Regnault. Carbonyl chloride; hydrochloric acid: Stark; Ramsay; Schoorl and Van den Berg; and Dott. Carbonyl chloride; chlorine: Brown; Schacht and Biltz; and Adrian. THE ~CHEMISTRY OF ANzESTtIETICS. 12 9

The formation of carbonyl chloride is alone definitely agreed upon. The decomposition of chloroform has been universally con- ceded to be an oxidation process. It is generally accepted that chloroform is unaffected by light alone, and that light, although it accelerates oxidation, is not a necessary factor in the process (Hager; Rump; Brown; Schoorl and Van den Berg) ; however, several investigators appear to have inclined to the view that light favors decomposition (Regnault; Dott). With regard to the changes which occur in anaesthetic chloroform during exposure to air and light, there also exists a decided diversity of opinion, principally owing to the fact that no exam- inations were made during the course of the various investigations, so far as we are aware, for the presence of the oxidation products of alcohol in such chloroform. The whole subject required investigation, and accordingly an experimental study of the decomposition of both pure and anmsthetic chloroform was carried out. It was also hoped to throw light on, if not fully explain, the r61e of alcohol 11 and other substances in the so-called preservation of chloroform, a satisfactory explanation of which has been wanting. Various samples, some twenty-three in. all, of both pure chloroform ~ and chloroform containing the usual pharmacopoeial amounts of alcohol and water, were exposed, .in well-stoppered 13 containers of various sizes, and containing varying amounts of the samples, and of both colorless and anactinic glass, such as are customarily used in the trade, for different

liThe amounts of alcohol stated as permissible in the various official chloroforms intended for anmsthetic purposes are as follows: Belgium ...... I.O per cent. Denmark ...... I.O per cent. Sweden ...... o.5-I.O per cent. United States ...... o.6-1.o per cent. France ...... o.oo5 part by weight. Italy ...... o.5 per cent. Switzerland ...... I.O per cent. absolute. This chloroform was prepared according to the method of the authors, and was absolutely pure. 1~ No cork stoppers unprotected by metal caps were employed. In the experiments on pure chloroform, glass-stoppered bottles were solely used. 130 CHAS. BASKERVILLE. periods of time, but at room temperature (20 ° C.), from Sep- tember to May, inside of a window having direct southern exposure. The conditions were extreme, but nevertheless were similar to those obtaining in many pharmacies and 'hospitals. The anaesthetic chloroform used was examined prior to the experiments, and only such chloroform as was found to be free from all impurities was used. However, an amount of water equivalent, on the average, to 5.I per cent. by volume of the alcohol present was permitted. 14 Thus each sample was of pharmacopoeial grade. The tests applied for the detection of the oxidation products of chloroform and alcohol were those previously proved out in our work. Quantitative determinations of the impurities developed were made when possible. The experimental results warranted the following conclusions : I. The products of the oxidation of pure chloroform are carbonyl chloride and hydrochloric acid, which come about according to the reactions:

CHC1, -[- H~0 -{- 0, : COCh + HCI + H,O, ; CHCh + H,O, = COCh + HC1 -]- H20. We are convinced that oxidation will not occur if water be excluded, and the absolute exclusion of moisture appears to be impossible ifl practice. Hydrogen dioxide is formed, although we have been unable to detect it in chloroform undergoing oxidation and therefore conclude that its existence is ephemeral, and oxidation of the chloroform continues throughout the period of the exposure. The r61e of the water is that of a true chemical catalyst. The decomposition of pure chloroform is accelerated by light, as was shown by a comparison of the results obtained in the experiments wherein colorless glass was used with those in which anactinic glass containers were employed. Carbonyl chloride is formed with increased readiness in the presence of acids, a5

14 The alcohol content of the amesthetic chloroform used was determined quantitatively by the method of Nicloux. 15Cf. Lowry and Magson, Trans. Chem. Soc., xciii, I2I, who observed that the formation of carbonyl chloride is evidently accelerated by the presence of acids. THE CHEMISTRY OF 2~kNcESTHETICS. ~31

The extent of the oxidation is dependent upon the nature of the container, the amount of air present, the purity of the sample, and the intensity of the light to which it is exposed. With light alone, when no air is present, no decomposition occurs for ordinary periods of exposure; and in cases where there is air contact alone, and no exposure to light, the oxidation is slow. Free chlorine can only result from the photochemical decomposition of carbonyl chloride. TM

COC12 ~--- CO + Cl~.

It is likely that in the cases where " chlorine " was identified as an indication of incipient alteration of chloroform, hydrogen dioxide was the cause of the reactions observed. No chlorine was found when containers of anactinic glass were used; and when chlorine is detected, it must be the result of a secondary reaction. 2. The products of the oxidation of ancesthetic chloroform are primarily the oxidation products of alcohol, and no decomposition of chloroform itself occurs while the oxidation of alcohol proceeds. When the oxidation of alcohol reaches a maximum, decomposition of the chloroform goes on as in the case of pure chloroform, with the exception that chlorinated derivatives of the oxidation products of alcohol may result. The decomposition of the chloroform itself is retarded, even prevented, so long as oxidation of the alcohol proceeds, and the retardation is consequently dependent upon the amount of alcohol present. The extent of the oxidation is subject to the conditions referred to in the Oxidation of pure chloroform. It is important to note, however, that anaesthetic chloroform always contains water, the usual amount being about 0.0 5 per cent. by volume, according to our experiences. At the inception of this investigation, it was considered possible that the instability of chloroform of all grades might be due to the presence of some catalytic agent, the removal of which would lead to beneficial results, as has been found in the case

*6Coehn and Becker, Ber., xliii, 13o; and Weigert, Ann. Physlk.. (4), xxiv, 55. The influence of light on the reversible reaction, CO + CI2 ~- COC12, is purely catalytic. 13 2 CHAS. BASKERVILLE. of sodium hypochlorite, 17 for example. We have arrived at the conclusion that, given proper purification, the chloroform prepared from chloral hydrate, alcohol, acetone, or carbon tetrachloride, is in all cases identical from an anaesthetic point of view and in decomposition products, as we know they are identical in chemical composition. But it was ascertained that the oxidation of alcohol is accelerated by the presence of oxidizable bodies in solution and that foreign organic substances have a detrimen- tal influence upon chloroform--which shows the necessity of having anaesthetic chloroform of a high degree of purity, from whatever source it may be prepared. This leads to the r61e played by ethyl alcohol in the preservation of chloroform, for alcohol does prevent the decomposition of chloroform, as first suggested by Squibb, in 1857, and later (1863) by Brown, independently. Those who have investigated the part played by alcohol in preserving chloroform up to the present time have held that either chloroform decomposes in the presence of alcohol and that the alcohol takes care of the decomposition products, or the alcohol acts as a "catalytic retarding agent" (Stadlmayr). The preservative action of alcohol is due to the combination of the retarder with certain of the reacting substances; and any substance soluble in chloroform and readily oxidizable will exert an inhibitory effect on the oxidation of chloroform itself, for example, sulphur and many other substances, is All compounds which have been found to serve as preservatives of chloroform are reducing agents, and the effect is only due to their capacity for oxidation. In the case of alcohol, inhibition develops with oxidation and retardation results until the oxidation of the in- hibitor reaches a maximum. Thus, when chloroform is "pre- served " with alcohol, the preservative is gradually consumed and is eventually totally destroyed, after which the decomposition of the chloroform itself proceeds as in the case of pure chloroform, with the exception that chlorinated derivatives of the oxidation products of alcohol may result.

17 The decomposition of commercial hypochlorite of soda is very largely due to the presence of small quantities of iron as ferrate in the liquor. Musspratt and Smith, J. Soc. Chem. Ind. (I898), xvii, lO96; (I899), xviii, 21o. xs Baskerville and Hamor, loc. cit. THE CHEI~flSTRY OF ANzESTHETICS. 133

The Stora9 e of Ancesthetic Chloroform.--An~esthetic chloroform should preferably be furnished in vials or bottles of high grade anactinic glass, 19 containing about the quantity sufficient for one narcosis, and at the most not more than can be used within several days. If, for any particular reason, chloroform is ordered in a large container, it is advisable, immediately after opening it, to subdivide the entire remaining contents into two-ounce bottles, taking care to fill the small bottles completely. It is important to see that the bottles are completely free from water, and empty bottles should not be refilled without thoroughly cleansing and drying them. In no case should chloroform be gradually withdrawn in small quantities from large bottles or carboys. When it is found necessary to store anresthetic chloroform, it should always be kept in a cool, dark place, in well-filled, or, better still, completely filled, tightly stoppered bottles of anactinic glass. The condition of officinal chloroform which may be trans- ported across the ocean and continent, or kept at sea for variable lengths of time, where it would be subjected to constant agi- tation, has been investigated. A:n~esthetic chloroform in un- opened, brown glass bottles were subjected to intermittent agi- tation for over 2oo hours in a Spiegelberg shaking apparatus, and it was learned from four samples so treated that it is desirable to prevent the presence of air, i.e., oxygen, being in associa- tion with this anaesthetic when it is robe shipped in the usual manner. Mouneyrat devised a method of displacing air by nitrogen, even making a nitrogen siphon of chloroform. The keeping qualities of anaesthetic chloroform may be seriously affected by the character of containers. The question of keeping anaesthetic chloroform in tin containers has been a much agitated one in the Federal War Department, and within the last ten years this Department has decided in favor of the tin container.

The glass should show no alkaline reaction when the bottle is filled with distilled water containing several drops of phenolphthalein solution and heated at IOO° C. for six hours. On the action of alkalies on chloroform, see Berthelot, Bull. soc. chim., (2), xxlx, 4; Andre, Compt. rend., eli, 553; de St. Martin, ibid., evi, 492; and Mossier, Monatsh., xxix, 573. It appears to be established that potassium hydroxide in alcoholic solution will slowly decompose chloroform. 134 CHAS. BASKERVILLE.

The opinion of the author is that glass containers are more conducive to purity for several reasons: First, in cleaning the vessels any foreign matters present may be readily observed and the bottles properly cleaned. Second, in the case of tins, some of the flux used in soldering may be introduced and thus impart an acid reaction to the chloroform. Hydrochloric acid accelerates the decomposition of chloroform. The introduction of this flux is also a problem in ether manufacture which requires the utmost care. Since it has been stated that spirit containing 95 to 96 per cent. by volume of ethyl alcohol is perfectly indifferent to tin, and tin .and tinned metals are absolutely unattacked by 90 per cent. denatured spirit, the tinned metals only being corroded where the tin layer is broken, 2° one would conclude that acid-free chloroform, ~1 containing the usual amounts of alcohol and water, would also be without action on tin, providing, it is stored in tin containers, having no broken or scratched surface, very carefully capped, and with a minimum amount of air. In order to determine this, a five-pound sample of chloroform containing 0.84 per cent. by volume of absolute alcohol and approximately 0.05 per cent. of water, which had been stored in a tin container, sealed, for sixteen months, was examined for the presence of tin. This sample left a residue non-volatile at IOO ° C., amounting to 0.0220 Gin. per litre, but none remained upon ignition and no tin could be detected in the sample. The examination of a sample of anaesthetic chloroform which had been kept in a sealed tin for six years also showed that no tin had been dissolved. In both cases, however, oxidation of the alcohol present had occurred, although no decomposition products of chloroform were present. Third, we have been informed by H. H. Dow ~ that he has "demonstrated that moist chloroform in the presence of a metal will slowly form traces of CH~CI2 and that it is pos-

*°Heinzelmann, Z. Splritusind., xxvii, 339. Malmejac, however (]. Pharm. Chim., I9OI, xiii, 169) found that a small amount of tin goes into solution in 95 ° alcohol after six months. = On the action of hydrochloric acid in chloroform on tin, see Patten, ]. Physical Chem., vii, 161, who found that the dry solutions act upon the metal less violently than upon zinc or aluminium, but more violently than on lead. Private communication. THE CHEMISTRY OF ANAESTHETICS. 135 sible to distil pure, dry chloroform in a metal container and produce a decomposition as shown by the following formula:

4CHCI, + 2Cu-= C2Ch + 2CH2Ch + Cu2Cl~. This reaction, however, takes place so slowly that it would never be noticed except in the handling of a material on which superla- tive efforts have been expended for years in order to get the last extreme of purity." Moreover, " all chloroform contains traces of CH2C12." In this connection, it should also be mentioned that it is probable that all metals which Show anomalous anodic conductivity are likely to develop free hydrogen dioxide in contact with water and oxygen ;2a in the author's opinion, the presence of such metals should therefore be guarded against in. the selection of a container for anaesthetic chloroform. 24 The Pharmacopoeia of the United States formerly required the use of " glass-stoppered" bottles, but subsequently changed this to " well-stoppered" bottles, thus allowing, the use of cork stoppers, a practice which has become general in this country. 25 The objections which have been urged against the employment of cork stoppers are two in number: First, the chloroform penetrates the cork after some time, especially during the agita- tion incidental to shipment, causing shrinkage and perhaps conse- quent leakage. Allain 26 and Masson 27 have recommended that when chloroform is kept in cork-stoppered bottles, a lute of "bichromate gelatin " should be used to prevent leakage. This is unnecessary when a proper stopper is used and the employment of lutings on the stoppers has led to differences between the manufacturer and consumer in the past. Only one of the many samples of anaesthetic chloroform examined by the author was contained in a bottle having a luted cork stopper, and in this case, considerable

'~All of the manufacturers of chloroform in this country use brown glass (" anactinic ") bottles. Of the eight different makes of German chloroform examined by the authors, only two were contained in colorless bottles. Barnes and Shearer, ]. Physical Chem., xii, 155, 468. In Germany, however, glass-stoppered bottles are used by prominent producers of anaesthetic chloroform (Kahlbaum; de Haen; Merck; A.-G. f/Jr Anilin-Fabrikation). =1. Pharm. Chim., (3), ix, 571. =Ibid., (6), ix, 568. VOL. CLXXII, No. IO28---II I36 CttAS. BASKERVILLE.

organic matter had been taken up, and, as a result, the chloroform failed to comply with the important sulphuric acid test or con- fused its interpretation. The second objection is that organic matter is extracted from the cork and the chloroform fails when the sulphuric acid test is applied. To obviate these difficulties, certain manufacturers of chloroform have adopted the plan of covering the bottom of the corks with tin foil, a procedure which so far has been found to be satisfactory, but which may be open to some of the objections to tin containers. Other manufacturers use a paper or parchment covering, and still others select only the best corks and extract them thoroughly with chloroform before use. The impurities of anaesthetic chloroform, so-called " organic impurities," are traceable to the materials used in the making, method of manufacturing, subsequent purification, manipulation before marketing, which may be grouped into one class (A), and those developed with different conditions of storage (Class B). These impurities, even though some may not be of much importance from a physiological stand-point, must still be given attention, since an impure chloroform is more likely to become altered through oxidation during storage, notwithstanding the fact that pure ethyl alcohol has been added. So far as we have been able to learn, the adulteration of anaesthetic chloroform is not practised now, and crude chloroform is no longer sold as chloroform of anaesthetic grade. In the first class (A) we have : Excess water ; Excess alcohol ; Acetone ; Methyl alcohol ; Carbon tetrachloride ; Carbon dichloride (C2C1,), carbon trichloride (C2C10), etc.; Aldehydes ; Amyl, propyl, and butyl alcohols, and compounds; Ether ** ; Acids (sulphurie, hydrochloric, acetic); Metallic chlorides ; Ethyl chloride ;

From I865-1875 ether was considered as one of the general con- taminants of chloroform. THE CHEMISTRY OF ANIESTHETICS. 137

Ethylene chloride ; Ethylidene chloride ~ ; Ethyl acetate ; Oils (" empyre.umatic,'~ "pyrogenous, .... chlorinated ") ; Fixed and extractive matter.

The possible impurities under the head of Class B are as follows : Acetaldehyde ; Acetic acid ; Carbonyl chloride ; Hydrochloric acid ; Hydrogen dioxide ; Chlorine; Chlorinated derivatives of alcohol oxidation products.

You are spared a discussion of the numerous tests for these substances, as that discussion would of necessity involve much detail and be of interest mainly to the analytical chemist. Suffice it to say that in our laboratory we have studied every test we have been able to find in the literature and have been forced to devise new ones in some cases, while in others, we are unable to make any recommendations at all as yet. Two illustrations may prove of interest. Paraffin oil, sp. gr. 0.88, may be used to discriminate between o.08 and 0.09 per ceflt, of water in chloroform, but it does not show the presence of a smaller amount. We are not aware of any test having been devised to show the presence of less than o.o5 per cent. of water in chloroform, until we found that crystals of calcium carbide would answer most satisfactorily. Carbon tetrachloride boils at + 78. I ° C. and has a specific gravitY of 1.63 ; chloroform boils at + 61.2 ° C. and has a specific gravity of 1.4989. A binary mixture containing 7.8 per cent. carbon tetrachloride boils at + 62 ° C. From what has been said of the presence of the variables, alcohol and water, in anmsthetic chloroform and their influence upon the physical properties of chloroform, it will be quite evident that determinations of these physical constants can be of little real value, and their application in general practice, even in well-equipped laboratories, is

About 188o ethytidene chloride was regarded as a general impurity of chloroform. 138 CrlAS. BASKERVILLE.

quite out of the question. All our efforts to secure a method applicable on a laboratory scale to detect small amounts of carbon tetrachloride in chloroform have been unsuccessful. To be sure carbon tetrachloride possesses anaesthetic properties, but it must exert its own specific physiological effect and the ames- thetist should know the drug he uses. Among the anaesthetic mixtures, the combination of chloroform vapor with oxygen was used shortly after the introduction of chloroform as an anaesthetic, and it has recently been rein- troduced into practice. Hence it was important to investigate the changes which anesthetic chloroform undergoes when a current of oxygen is conducted through it. Dr. J. T. Gwath- mey s0 has recently stated that oxygen increases the value of all inhalation anaesthetics as regards life. Several experiments were carried out in order to determine whether the passage of a current of oxygen through anesthetic chloroform brings about decomposition of the anesthetic. Ames- thetic chloroforms containing o.56 to I.o per cent. of alcohol and o.o3 to o.o5 per cent. water were used. The conditions were such, except that the temperature was about + 2o ° C., as obtain during administration by the Gwathmey method, his apparatus being used. The oxygen was allowed to flow at such rates througta 3I~ to 4 ounces of the anesthetic that about one-half remained in the vapot'izer after 3~ to IO~ hours. In one experiment the chloroform vapor was passed through water as is Dr. Gwathmey's practice, and subsequently condensed. The examination of the residue and condensed chloroform showed the following :

Acidity (acetic acid) : Chloroform used ...... none. Residue in container ...... o.oooi5 g. in Ioo c.c. Condensed chloroform ...... none.

Sulphurie acid test: Chloroform used ...... negative. Residue in container ...... marked reaction. Condensed chloroform ...... negative.

~o The writer has been collaborating with Dr. Gwathmey, who has directed the clinical observations. THE CHEMISTRY OF ANESTHETICS. i39

Therefore it was concluded that the oxidation products of alcohol are not carried over when the chloroform-oxygen stream is conducted through water, and that these are concentrated in the residue. By this method of administration the patient is pro- tected from the objectionable decomposition products even if they have developed. Furthermore, the vapors of the anaesthetic so applied are saturated with water, hence cannot exert that dessi- caring effect upon the mucous membrane they would if not moisture laden.

OXYGEN. As animadverted, ninety-four years after the discovery of nitrous oxide and oxygen by Priestley, they were first used in combination for anaesthetic purposes. Although Andrews published accounts of several cases in which, by mixing oxygen with nitrous oxide, he had obtained a more satisfactory form of an,'es- thesia than with nitrous oxide alone, his observations failed to attract the attention they deserved. Ten years later (I878) Paul Bert drew further attention to this form of anaesthesia. Hewitt 31 stated, previous to the completion of the work reported this evening, that the most recent and best development in modern anaesthetics is the combination of oxygen with nitrous oxide, whereby a non-asphyxial and safe form of anaesthesia may be produced. The results of a long series of experiments with various anaesthetics and different mixtures caused Gwathmey to

say " Oxygen is indicated with every anaesthetic and at all times. The longer the anaesthesia, the more urgent is the call for oxygen by the blood." The importance of the purity of the oxygen used is apparent. The alchemists 32 were probably acquainted with oxygen, perhaps also the Greeks 33 in the fifth century, and the Chinese, 34 long before Priestley's experiments. In I63O, Jean Rey 35 knew that certain metals, when heated, fix a portion of the air, and in

8~,, Anaesthetics," The Macmillan Co. Bolton, Am. Chem., iv, I7o. s, Hoefer ' Histolre de la Chimie, ii, 27I. Duckwood, Chem. News, liii, 25o. Jean Rey, Essai sur la recherche de la cause pour la quelle l"estain et le plomb augmentent de poids quand on les calcine, Bazas, I63o. 14o CHAS. BASKERVILLE.

1674 Mayow ~6 prepared oxygen from nitre. In 1771, Scheele 3r prepared the gas by heating several oxides including the black oxide of manganese, and at about the same time Cavendish 38 studied oxygen. To Priestley189 however, has been given the honor of discovering oxygen as a constituent of the air. Davy 4o and Lavoisier 41 later studied the preparation and nature of this gas. At the present time there are the following methods of preparation and manufacture of oxygen: 42

i. Heating chlorates; 2. Heating chlorates with various substances; 3. From hypochlorites and reaction of chlorine and water; 4. Heating sulphuric acid or sulphates; 5. Heating various solids and mixtures (MnO2, CuB40~, etc.) ; 6. Combustion of solid mixtures (chlorates with combustible material, alkaline peroxides with hydrated salts, etc.) ; 7. Reaction of peroxides (ozone) with water and aqueous solutions; 8. By electrolysis of water; 9. From the air by means of mercury, cuprou*s chloride, barium dioxide; manganates, plumbates, or living matter; dialysis or absorption; and Io. From liquid air.

Oxygen that is to be used in anaesthesia should contain at least 95 per cent. 02 upon the dry basis. We found the pyro- gallate method for the determination of oxygen the most con- venient to employ and most satisfactory provided Hempel's 43 precautions to prevent the production of carbon monoxide are taken.

:'~ Rodwell, Chem. News, viii, 114. ~ Abhandlung yon der Lu[t und dem Feuer, Upsala u. Leipzig, 1777. Trans. Roy. Soc., lvi, 432; lxxiv, ii9~ 17o ; IXXV, 372. 8~ Trans. Roy. Soe., lxii, 147; lxv, 384; lxxiii, 398; lxxv, 279; lxxviii, I47, 313; lxxix, 7, 289. "Experiments and Observations on Different Kind of Air," London, 1775-1777, ii, 29 ; iii, I ; " Experiments and Observations Relating to Various Branches of Natural Philosophy," London, 1779, i, 192. 4o Trans. Roy. Soc., ci, I. "1Chem. f. (Crell), iv. 440; v, 125, Crell. Chem. ,4nn. (I786), i, 33, 136; (I788), i, 354, 441, 528, 550, 552; ii, 55, 262, 431, 433; (I789), i, 145, 162, 26o, 323; ii, 68, 145, 433; (I79O), i, 69, 518; (I79I), i, 71; (I8O3), i, 29. " Baskerville and Stevenson, f. Ind. and Eng. Chem., iii, No. 7. ,a Hempel, "Gas Analysis," English translation by Dennis, 19o6, p. I49. THE CHEMISTRY OF AN.~STHETICS. I4I

The following sorts of matter may be suspected to exist in a cylinder of compressed oxygen: I. Solids. 2. Liquids. 3. Gases and vapors: H,O, Halogen acids, HNOs, organic acids, 0,, NO~, N~08, SO,, NH,, organic bases, CO~, halogens, oxides of chlorine, HCN, (CN),, PH.~, SbH~, ASH3, H~S, H2, CO, CH,, organic matter, N,, N20, rare gases of atmosphere. For these impurities, some of which are harmless from a physiological point of view, a qualitative search should be made

TABLE X.

Source of Organ- [ I Allother No. oxygen. 02 H20 C02 H2 ic mat- 12,etc. impuri-ties.

I KC103 + MnO2 93.20 0.30 0.II 0 6.39 o 2 KC108 + MnO2 98.3 I O.I4 present 0 ':I,1.54 o KC103 + MnO2 92.82 0.26 trace 0 6.92 o KCIO3 + MnO~ 97.I3 0.2 3 present 0 trice ' 2.63 o Liquid air 96. Io O.I 5 0.01 0 3.74 o Electrolysis 99.23 0.35 0.03 O.I4 0.25 o 7 [ Na202 ÷ H20 99.20 0.50 trace O 0 : o.3o o and then, whenever necessar)r, a quantitative determination. A systematic procedure was devised which need not be gone into here. Nitrogen and the " noble gases " may be determined by difference. It may be mentioned that no sensitive test is known for nitrous oxide. Analyses, by our methods, of oxygen on the American market gave the results shown in Table X.

CONCLUSIONS. I realize the danger of a mere chemist making an excursion into the field of medicine, but the extremely venturous one, if he has luck, may be swept by the rocks of which he is supposed to I42 CHA$. BASKERVILLE. have little knowledge. But I have done enough in this field to make me take a theoretical plunge. Modern studies in physiology have unquestionably shown that the animal body exists to a great extent by virtue of the chemical and physical changes going on within it. I know of no valid reason for assuming that these changes are essentially different from those we control in the laboratory. If we wish to duplicate or control a physical or chemical change in the laboratory, we must become familiar with all the factors and conditions. I know of only one class of such changes over which we have not as yet secured control, and in that class belong those processes which we term radio-active. I am not sure but that we even have indications pointing toward our control of these. One of the essential factors in controlling a chemical process is the quality of the material with which we are working. I cannot therefore but regard all published statistics as to the mortality attributed directly to the anaesthetic used as more or less worth- less and that a large number of new cases must be observed to secure knowledge of the real physiological effect of the drug when carried into the system by the pulmonary route. Impure foods, sophisticated intentionally or otherwise, may bring on disease. Impure drugs, concocted or otherwise, fail to produce the full effect planned by the physician in curing disease. I feel that the great lack of uniformity among th.e pharmacopoeias of the world need not obtain, especially where the analytical methods are involved. True, as Remington has maintained, "the Pharmacopoeia is a book of standards for medi- cines, and not for analytical chemists," yet the methods of standardizing should be comprehensive, accurate, and reliable, as well as rapid and as simple as possible. It is unquestionably impossible for every pharmacist to determine the quality of all his chemicals and drugs, but the druggist may easily apply simple tests to determine the purity of many, especially when these tests are decisive and simple. While the dispenser must largely depend upon the reliability of the manufacturer, he should, like the physician, be familiar with the changes which chemicals un- dergo when improperly stored, in order that he may not allow impurities to develop and may guard against their formation. What a step modern civilization would take, if the leading nations THE CHEMISTRY OF AN2ESTHETICS. 143 decided to put forth an international standard pharmacopoeia, revised in full each decennium, with annual supplements! Idiosyncrasy has served to account in large part for unto- ward after-effects of anmsthetics and certain disagreeable conse- quences, as nausea and interference with some of the normal organic functions, as glycosuria and albuminuria; these have often been regarded as natural results of anresthesia and taken for granted. They may now be largely obviated, and in many cases entirely avoided, by the use of anaesthetics that are free from impurities, and by improved methods of administration. These statements are based upon clinical evidence. The main objectionable constituent in ether is acetaldehyde. American official ethers call for three to four per cent. of ethyl alcohol in accordance with an old theory. Alcohol is practically never free from water, and in the presence of water and oxygen forms oxidation products. The speeds of the changes depend upon conditions. It has been shown that the administration of moist ether, free from aldehyde, at body temperature, is rarely followed by nausea (less than ten per cent.) and the usual strain upon the kidneys is not observed. Chloroform was formerly made mainly from alcohol and contained many of the normal impurities of the alcohol used. These were not removed by the methods of purification practised, nor are they removable now, except by elaborate methods of purification. These impurities doubtless have had much to do with the feeling of uncertainty in administering chloroform. Pure chloroform undergoes decompo.sition when exposed under certain conditions, such, for example, as the manner in which anresthetic chloroform is dispensed in some drug stores and hospitals. A suitable amount of alcohol prevents this decomposition, shunting the change in composition to itself; hence anesthetic chloroform should contain ethyl .alcohol. But the conditions of transportation andkeeping of this chloroform should be such as to reduce the change of alcohol to aldehyde and acetic acid to the minimum. Nitrous oxide, ether, and chloroform, each exerts its specific physiologic effect in producing anaesthesia without asphyxiation, provided the respiratory and cardiac functions are maintained approximately normal. This may be, and is being, accomplished by administering these gasified drugs with sufficient oxygen not I44 CHAS. BASKERVILLE. to interfere seriously with the normal function of the h~emoglobin of carrying oxygen to the capillaries and by maintaining the usual concentration of carbon dioxide in, and providing its regu- lar elimination from, the blood. Other factors involved are temperature and moisture. The amesthetics are carried into the system at body temperature. This may be and is being accomplished by warming, and, in the case of ether and chloroform, by passing the vapor through heated water, which, at body temperature, not only removes the aldehyde, but saturates the gas with moisture (Gwathmey method). The osmotic action of the alveolar cells is thus affected only to the extent of the densities of the gases introduced into the lungs and not, as normally is the case, by temperature (always lower) and dessication as well. In other words, by the application of the principles of modern physical chemistry, the numerous variables are so reduced as to secure the real physiological effect of the particular anaesthetic drug after it enters the system. Nitrous oxide and oxygen may be used for prolonged anaesthesia and successfully for eighty per cent. of surgical cases; furthermore, ether and chloroform may be used with equal safety. The real, and no supposititious, idiosyncrasy of the patient may be met. The expert anaesthetist may now not only make it possible for the surgeon to perform even greater miracles, but with more comfort to himself in his work, and with greater happiness and less discomfort to the patient.

Study of the Firefly..H.E. IvEs. (Phys. Rev. xxxi, 637. )- In conjunction with Coblentz the author has described an investigation of the visible radiation from one variety of firefly (Photinus pyr- alis). This investigation differs from previous ones in the application of photography with color-sensitive plates. There are grounds for believing that the firefly's visible radiation is its total radiation. Experiments in the infra-red and the ultra-violet regions of the spectrum are described. The region from o.2# to 1.5# was explored. The only radiation was in a narrow band at o.57t~ as previously found. The abdominal skin of the insect is proved to be transpar- ent as far as 3. The light is apparently under the control of the insect and has none of the properties of true phosphorescence, but is due to some bio-chemical process, which there is no reason to sup- pose cannot be artificially produced by man.